The CD27 and CD70 costimulatory pathway inhibits effector function of T helper 17 cells and attenuates associated autoimmunity

Immunity. 2013 Jan 24;38(1):53-65. doi: 10.1016/j.immuni.2012.09.009. Epub 2012 Nov 15.

Abstract

T helper 17 (Th17) cells protect against infection but also promote inflammation and autoimmunity. Therefore, the factors that govern Th17 cell differentiation are of special interest. The CD27 and CD70 costimulatory pathway impeded Th17 effector cell differentiation and associated autoimmunity in a mouse model of multiple sclerosis. CD27 or CD70 deficiency exacerbated disease, whereas constitutive CD27 signaling strongly reduced disease incidence and severity. CD27 signaling did not impact master regulators of T helper cell lineage commitment but selectively repressed transcription of the key effector molecules interleukin-17 (IL-17) and the chemokine receptor CCR6 in differentiating Th17 cells. CD27 mediated this repression at least in part via the c-Jun N-terminal kinase (JNK) pathway that restrained IL-17 and CCR6 expression in differentiating Th17 cells. CD27 signaling also resulted in epigenetic silencing of the Il17a gene. Thus, CD27 costimulation via JNK signaling, transcriptional, and epigenetic effects suppresses Th17 effector cell function and associated pathological consequences.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity / genetics
  • Autoimmunity / immunology*
  • CD27 Ligand / genetics
  • CD27 Ligand / metabolism*
  • Cell Differentiation / immunology
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Epigenesis, Genetic
  • Gene Expression Regulation
  • Gene Silencing
  • Interleukin-17 / genetics
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism
  • MAP Kinase Signaling System
  • Mice
  • Mice, Transgenic
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Receptors, CCR6 / genetics
  • Receptors, CCR6 / metabolism
  • Signal Transduction*
  • Th17 Cells / cytology
  • Th17 Cells / immunology*
  • Th17 Cells / metabolism*
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / metabolism*

Substances

  • CD27 Ligand
  • Interleukin-17
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Receptors, CCR6
  • Tumor Necrosis Factor Receptor Superfamily, Member 7